Most promising synthetic modifications

[resorcinol]

of opioids?

I'm very interested in 14 substitutions of opioids with the phenanthrene core structure (ie, opioids that closely resemble morphine chemically -- all opioids to a degree share structural patterns in common, that's how they can all activate mu receptors, but I mean the ones where that phenanthrene backbone JUMPS OUT at you).

The one in my signature is an example of one such opioid. It's hydromorphone substituted with methyl at pos 5 and phenylpropoxy at pos 14 and is massively more potent, similar to etorphine.

It's not just increases in potency that 14 substitution confers that interests me, though. Anecdotal evidence seems to suggest that the 14 substituted, and much revered, opioid called oxycodone has less of a body load and over-sedation than opioids that have just hydrogen there (morphine, hydromorphone, hydrocodone, etc). Oxycodone and oxymorphone (another 14 hydroxy substituted opioid), are both revered for their intense euphoria in their class. Oxycodone is considered by most people to be the most euphoric "codone" by far, and oxymorphone beats the rush of dilauded (hydromorphone) according to those lucky enough to have had it via IV.

Esters of oxycodone at the alcoholic 14 hydroxyl group could be drugs that are both very potent and have awesome oral bioavaliability. Among common opioids in medical use only oxycodone has both of those properties, and that is why it is so popular. We could, however, get stronger opioids than oxycodone by esterifying that 14-OH -- oxycodone isn't THAT strong. Imagine a fentanyl strength opioid that can be taken orally without wasting it. 14-cinnamyl-oxycodone is very promising for potency and bioavaliability.

So yeah, I've got a fetish for substitutions at that position. I actually get all excited when I see a functional group in place of a hydrogen in that little corner of a synthetic molecule.

[rockbottom]

bring it on doc--i wish i could understand 1/2 of what u said:)

[BigPoppy]

Dude, We read your post all the time and no one has a clue what the hell your talking about. I want what your on :)

[resorcinol]

It seems like modifications at this position on morphine-style opioids is the only way known so far besides the Bentley compounds to get fentanyl like potency opioids in this class.

Benley compounds introduce that side chain at position 7 and another six membered ring jutting out from position 6 to position 14. Hmm... even with the bentley opioids there is a modification at position 14. Clearly, it's an important spot for agonist activity at mu receptors. Some bentley opioids are etorphine, dihydroetorphine, and buprenorphine (a bastard child of the bentley opioids... that N substitution, the methylcyclopropyl one, makes it a partial agonist and not a full agonist). Normally, an N substitution like the one in buprenorphine would make for an antagonist (look at naltrexone), but the extra ring from 6 to 14 and the 7 side chain are such powerful agonist-favoring modifications, that buprenorphine is saved from being an antagonist and is a partial agonist. It's still a bastard child though, partials are yucky compared to full agonists. Although as partials go, bupe is a decent one... it seems to lean more towards the agonist side than, say, nalbuphine and butorphanol, which are really nasty and unpleasant.

Ya know what surprised me when I read it? delta-9-THC is a partial agonist at CB1 receptors, not a full agonist. There are synthetic cannabinoids out there like WIN 55 212-2 that are full agonists at CB1, and water soluble in salt form too. Man, if those became popular desinger drugs, weed could be relegated to second place. Although, stoner culture likes "natural plant" stuff a lot, so cannabis could be saved by that.

[resorcinol]

I know double posting is discouraged, but I really want to add something. Even though there haven't really been any serious responses to this thread yet, sometimes I like to just muse over things in the chemistry section here.

There's no more profound insight into opioid SAR in this post, just a statement derived from the posts above about 14 substituted semisynthetics.

Going beyond a simple hydroxide group at position 14 (oxycodone has a simple -OH at pos. 14; that's the only difference between it and hydrocodone) can result in extremely potent -codone opioids. Codeine's pathetic potency has given the impression that an ether at pos. 3 on morphinans destroys activity as a mu agonist. With morphine, this is true, it's 3-methylether (codeine) is a very very weak mu agonist. When there's a double bond a pos 7 to 8 and a simple hydroxide a pos 6 as in morphine, substitutions of the hydroxide at pos 3 really destroy most of the opioid activity.

However, with a single, saturated bond between pos 7 and 8 and a carbonyl at pos 6 instead of a hydroxide, substitutions at pos 3, including a methylether, have a much less extreme deleterious effect on potency. These codeine derivatives, -codones, have intrinsic mu agonism far greater than that of codeine. This is why hydrocodone has largely displaced codeine... metabolic deficiencies don't influence analgesic efficacy and side effects are far less. Also, since these "codones" have significant intrinsic mu agonist activity, the door is open for modifications, where codeine is a dead end street because in codeine's case, the 3 methylether practically completely abolishes activity. You can't polish a turd, as they say.

While the "morphones" are still much more potent than the "codones", the codones have one clear advantage... they've got much, much better oral bioavaliability (and usually better nasal bioavaliability too). Oxycodone was the first codone to be viable for long term relief of severe chronic pain. It's pos 14 -OH makes it suitable to replace morphine when that is desired, and is actually preferable to morph when the ROA is oral by a longshot. Hydrocodone fell JUST short of the potency needed for relief of CP long term, but oxycodone fixed that with a simple -OH at pos 14. The "codones" can be modified to increase potency in other ways besides making them morphones, because making them morphones by removing that pos 3 methyl ether destroys oral bioavaliability and reduces usefulness as oral medications.

The prime method that I see to optimize codones is going beyond simple pos 14 -OH functional group. By esterifying that group, we can get painkillers that beat oxymorphone in potency and retain their high oral bioavalibility thanks to the protection that pos 3 methylether offers against first pass metabolism.

Esters of codones at pos 14 could revolutionize pain management with oral meds if the pharma companies pursue it.

It's just amazing that potent, orally avaliable to the bloodstrem painkillers, can be made that were modeled after codeine, a drug that is useless for all but mild pain.

[Hoss]

Ok, this might sound like a really stupid question, but seeing as how there are people in this world with such knowledge and understanding like Resorcinal & Robojunky to name a couple, are there people out there that act out some of these concepts on their own and create some of these opiates clandestinely in home/illicit-labs? Or is it too difficult/dangerous/not possible? I honestly don't know a thing about chemistry although I wish I did, and thus I have always wondered if it was possible. Again, this is just pure curiousity.

I was always curious about this after hearing about clandestine Fentanyl - always wondered, albeit how dangerous such could be. Guess it's part of the junky fantasy.

[Narkotikon]

I think it's that they just really like learning about pharmacology. I can see some people trying to synthesize this stuff, but I think in this case it's just that they're really interested in it and find it enjoyable.

I admit though that I don't understand half of what this stuff is. I like learning about some pharmacology, but when it gets into the chemistry and substitutions of molecules and things like that, I'm completely lost. I don't really care how a drug works as long as it works on me. :-)

[robojunkie]

Here's one for ya resorcinol, look at the structure you have of the phenylpropyloxy derivative of oxy. One could make this without any problem with oxymorphone (BBr3 and oxy) by simply adding some phenylpropylbromide to acetone, potassium carbonate and acetone. Just stir the shit at room temp for enough time so see solid shit crash out. Done.

Good luck finding the phenylpropylbromide though. Technically you'd have to do the demethylation last to prevent making some inactive bis-ether.

Hoss, it is possible for one to do such things, but in all seriousness there are major risks involved, legally and personally, it is nearly impossible, thought not absolutely so, to avoid a paper trail to be used against you later, and requires years of experience to do any multistep original synthesis. Even derivative syntheses with multiple steps take years of experience, hell even people with a little experience can botch up a meth cook and that's gotta be the easiest there is, with morphine to heroin being a close second. Never order chemicals from a chemical supply house, watched or not! Adapt and Survive, its possible!

[stvip]

What's the point of focusing on all these ultra-potent compounds? The lethality of these chemicals are in the chemical weaponry range (seriously, these qualify as WMDs, and see http://en.wikipedia.org/wiki/Moscow_theater_hostage_crisis for an example of mass-casualty related event).
Of course the discussion and speculations are interesting,and there's no harm sharing information.

However, my approach (before deciding to abstain from making science-relateds contributions to Opiophile, which I'll explain in a summary post soon) was on the contrary, to find simple, easy available, safe and diverse methods by which the layman canacquire or enhane opioids.

In a constructive enviornmnet with honest people (not Opiophile), you'd be surprised to what degreean online community is capable of introducing and spreading such methods. A very nice example is how psychedlic mushrooms (mainly Psilocybe sp.) cultivation techniques have been introduced and popularized via The Shroomery. Prior to this success story, I bet the vast majority of scientists would have been inredulous that amateurs could manage to isolate and safely grow a fungal microorganism (which requires the transportation of sterile spores, and uneducated, inexperienced people sucessfully implementing imrpovised lab equipment in order to carry out sterile laboratory fungi cultivation protocols).

[clinton]

sounds interesting..at least the part that i understood

[chemchem]

Great post.

I would really like to get the crystal structure of these receptors and load them up on the computer. I bet there is a nice pocket that fits all those subs. on the 14 position. Its amazing how many areas you can modify, it should be plausible to optimize a structure that is highly selective and specific.

Do you know of any papers that address 14-substitution? It would be interesting to see what other modification were made and how that activity compares. It shouldn't be too hard to put something on the 14 once you get an oxygen there. I would imagine this could be an easy step taken to increase potency.

I often wonder how an acetyl group would work there. Its possible esters might be better, and they should make it easier to cross the BBB. It would be interesting to see the effects of the acetylation of oxymorphone (I have an article where they perform the chemistry but not the biology).

Anyways, it may not be the best idea to have super potent drugs to be taken orally as you never know exactly how a persons enzymes will work.

I should really read the articles I have.

[robojunkie]

stvip, this discussion is of course academic, I could write out a full detailed six step fentanyl synthesis using commonly acquirable materials (except for propionyl chloride, always wathced with dea on the tail of the shipment) with step by step instructions, structures, little tips at where problems would creep up and so forth and it still wouldn't happen for all but the very few professional chemists, who if qualified and daring enough, could probably (or possibly, I don't know the insights of the minds of others of course) achieve success, but would result in an utter catastrophe (where nothing dangerous or effective would ever be gotten to) for the average person. In other words, knowledge and experience in synthetic chemistry is absolutely required to pull this shit off, hell even the above mentioned phenylproyl-etc idea would be unsuccessful without knowledge of why each thing is there, how much, work up and purification, and so forth. Not to mention its an obscure chem, no non chemsupply house source I can imagine.

In other words, this aint the opiohive, if it were I probably wouldn't contribute without all the paranoid trappings of proxies and all the other anonymocomputer stuff I never bother with. Most of this discussion is of course for academic purposes and the fantasies of us junkies anyway. IMO if someone is qualified to attempt the bigtime complex and drawn out syntheses they need no helphere or on any other website. All the resources, theoretical and if one takes the longview, experimental, are out there, they just must be aspired to and worked for with great diligence and perseverance. There is no easy way to do these things, as I'm sure you can imagine anyways.

[resorcinol]

stvip, this discussion is of course academic, I could write out a full detailed six step fentanyl synthesis using commonly acquirable materials (except for propionyl chloride, always wathced with dea on the tail of the shipment) with step by step instructions, structures, little tips at where problems would creep up and so forth and it still wouldn't happen for all but the very few professional chemists, who if qualified and daring enough, could probably (or possibly, I don't know the insights of the minds of others of course) achieve success, but would result in an utter catastrophe (where nothing dangerous or effective would ever be gotten to) for the average person. In other words, knowledge and experience in synthetic chemistry is absolutely required to pull this shit off, hell even the above mentioned phenylproyl-etc idea would be unsuccessful without knowledge of why each thing is there, how much, work up and purification, and so forth. Not to mention its an obscure chem, no non chemsupply house source I can imagine.

In other words, this aint the opiohive, if it were I probably wouldn't contribute without all the paranoid trappings of proxies and all the other anonymocomputer stuff I never bother with. Most of this discussion is of course for academic purposes and the fantasies of us junkies anyway. IMO if someone is qualified to attempt the bigtime complex and drawn out syntheses they need no helphere or on any other website. All the resources, theoretical and if one takes the longview, experimental, are out there, they just must be aspired to and worked for with great diligence and perseverance. There is no easy way to do these things, as I'm sure you can imagine anyways.

Agreed man, I think my main motivation for posting this stuff is academic interest and sheer fantasy about unlimited supplies of opioids.

Potent opioids mean:
1)Greater number of highs from smaller amount of precursors. A lil vial of powder could last for years.... years of bliss in a teeny tiny package

2)Extremely potent drugs are MUCH easier to conceal, and could be dosed by dilution of the salted drug in water and application, dropwise, onto blotter

3)Drug dogs aren't trained to smell 14-cinnamyl-oxycodone, ohmefentanyl, 14-phenylpropoxy-5-methyl-hydromorphone, pentamorphone, etc, etc.

Things like that play into the fantasy. Actual synthesis is a diff ballgame. I do have some actual knowledge of orgo and reaction mechanisms (did well in orgo chem I and II), but that's nowhere near enough knowledge of orgo for complex drug synths. Even knowing a possible synthetic route is pretty useless without hands-on experience in the lab, which I really don't have. Then there's the legal ramifications if caught, which are so much more massive than possession of common controlled drugs, an still more severe than being caught dealing common controlled drugs.

It's a curiosity about opioids, and opioid SAR (structure activity relationships).

Chemchem, I agree that the groups on position 14 that clearly enhance potency either a little or a lot depending on the exact substituent seem to suggest that those groups fill a pocket in the mu receptor that helps the drug seat itself more neatly into the receptor. Since hydrophobic and somewhat bulky ester and ether substitutions seem to result in the greatest potency increases, it's likely a rather large hydrophobic pocket in the MOR. -OH enhances potency a little (see oxycodone and oxymorphone's structures), but esters and ethers thereof enhance potency many orders of magnitude more than the simple -OH. Some substituents without an oxygen bridge like ethers and esters have also greatly enhance potency. Look at the structure of pentamorphone (picture provided below); it is 14 substituted with a pentylamine group, the nitrogen side being bonded to the 14 position:

pentamorphone -- somewhere around 400x more potent than morphine
http://upload.wikimedia.org/wikipedia/en/thumb/f/f9/Pentamorphone.png/220px-Pentamorphone.png

It's just all very fascinating stuff. I really love opioid SAR, and benzo SAR too. Opioid and benzo SARs are far more interesting than amphetamine like stimulants SARs, IMO.

[Hoss]

To be completely honest with you, when I would see these technical looking "Chemical Posts" I would be interested in the content itself, and would 'try' to start reading it, but to no avail as my attention span concerning topics I do not understand can run thin at times. However, I really AM starting to dig these posts! I mean, I really don't know what the hell all of the actual terms are that you guys are talking about, but it does interest me.

So... I have a couple of questions :

1.) I have no chemistry experience or background whatsoever, but, are there any online sources/guides you would recommend to get the very basics of chemistry instilled in a mind like mine, whom has no experience? I know I can Google up such, just wanted to see if you guys had any certain sites/etc. you would advise. I have no desire besides "fantasy" on ever acting out on any knowledge, and ask for assistance in understanding such only out of the desire to be able to perhaps fathom the very text you guys write here, that's all. I would not know what the hell to do in a lab, clandestine or not, I just want to understand the concept as is.

2.) Now this question has to do with that horrible event that occurred in Moscow back in 2002 with the Fentanyl gas being pumped into the theater, killing many if not all - what if you were on a high dose of Buprenorphine while inside the theater while the gas was pumped in? Would the Bup block the Fentanyl from being absorbed or would the Fent "break through" if in quantitative amounts?

For my second question this is again obviously out of pure curiousity, as I feel for the innocent individuals who parished. I am wondering about the effects of such concerning opiates being used as WMD's - could an imposing "force" or Army then just fit their soldiers with Bup or an antagonist? Then what would happen if they were wounded in battle or combat and needed opiated pain relief?

Just a couple things that this thread got me thinking of.

[Narkotikon]

I don't agree with the use of opiates as WMD, or any chemicals for that reason. But, I will say that if I had to go, I'd rather go from Fent gas than something like Sarin gas or other nerve agents.

That's interesting about the Bupe / antagonist thing. I'm not sure if it would work. I think the Bupe would work well at blocking a small or even moderate dose of fent, but if you're in a room full of fent gas and breathing in huge amounts, I don't think it would block it for long. I think the fent would eventually win out. It is more potent than bupe, although I don't know if fent's binding affinity is higher than bupe. I know that bupe has a really really high binding affinity, not exactly sure what fent's is, although I'd guess it's pretty high too. Although I do know that bupe isn't as potent as fent. I think 200 / 300ug is the standard dose for bupe, and it's something like 25ug or 50ug for fent for an opiate naive person. IV speaking of course. I know that in cases of Fent OD's, where the people were injecting fent that they really thought was heroin, that it usually takes a lot more Narcan to get them out of it than it would heroin. Aside from actually testing for the fent, that's another way they can tell it's fent and not H. It takes more Narcan to get them out of the OD than it would for a simple H overdose. I'm not sure if there's a stronger antagonist than Narcan. I'm not sure if Narcan itself would work to block a room full of fent gas. Plus, is this gas regular nublized fent, or is it an analog of fent, like carfentanyl or something like that. Hell, if they're going to use opiates for WMD, they should just use etorphine in gas form. That would be fucking scary. No way you're living through that.

[Hoss]

Hell, if they're going to use opiates for WMD, they should just use etorphine in gas form. That would be fucking scary. No way you're living through that.

Crazy - Etorphine is approximately 1000 the potency of Morphine and according to Wikipedia :

"Veterinary-strength etorphine is fatal to humans; one drop on the skin can cause death within a few minutes.[4] (http://en.wikipedia.org/wiki/Etorphine#cite_note-3)"


http://upload.wikimedia.org/wikipedia/commons/thumb/6/64/Etorphine.png/220px-Etorphine.png

[robojunkie]

They say that it was carfentanyl that was used in the Moscow opera house disaster. However some dispute this and one group couldn't find evidence of this in blood samples (though not much would have been needed). Probably only carfent, etorphine and the "correct" ohmefent isomer would work like this as they aren't volatile as is they have to be nebulized and to reach the concentrations to cause OD's I've read that regular fent just wouldn't cut it. Fuck this use though, as if we and our drugs don't already have enough scapegoating attached to them last thing we need is association with the ethereal WMD concept. Opiates are the chemistry of peace and love not war and destruction!

[resorcinol]

^ Damn straight, robojunkie!

The thought of potent opioids like these we're discussing being used as weapons didn't even occur to me. I was only thinking of using them for fun with super careful dosing with the potent ones. This is all about optimizing the fun potential of opioids!

The thought of wasting opioids makes me nauseous -- wasting them through warfare is even worse. ugh.

[resorcinol]

One more broad observation about 14 substitution -

The most potent substitutions add a kind of tail thing to the molecule with an aromatic ring on the end of the tail. They elongate the molecule in this specific way. Remind you of anything? Take a look...

http://upload.wikimedia.org/wikipedia/commons/thumb/1/1c/Fentanyl-xtal-2D-skeletal.png/220px-Fentanyl-xtal-2D-skeletal.png

That's our friend fentanyl.

Now there are important differences, but look at the compound in my sig and fentanyl, and tell me you don't see a pattern? At least two ring systems close together looks necessary for potent mu agonist binding (tapentadol has one ring only but it's not a potent agonist by any means)...more rings fused or in the vecinity of the core of the molecule are A-OK as long as they're situated correctly in 3D space.

But it seems that to get a super potent opioid, you need that TAIL with an AROMATIC ring on the end of it, sticking off at the right spot in 3D space, which on fentanyl is off the N on the piperadine ring and on morphinans off the 14 carbon.

Etorphine like opioids are the exception, but they have an additional ring system that complicates things, and a 7-side chain. So I'm conveniently ignoring them atm.

The similarity in apperance of fent and the one in my sig is striking if you're seeing what I'm seeing.

I betcha p-fluoro-14-phenylpropoxy-5-methyl-hydromorphone would be even more potent, just like the fent analogs with p-fluro on the phenyl ring on the tail off the piperadine.

[Paregoric Kid]

that is interesting and I think the hydromorphone analogs like metopon and acetylmorphone sound beautiful. but I think people should concentrate their efforts at discovering opioids that would be legal because of not being an analog of anything that is schedule I or II or anything scheduled at all. these things are interesting and all and would be great to do but an easy synth that could produce a legal opioid would be invaluable. in the US the analog act is supposed to only apply to things that are analogs of a CI or CII substance, not III or IV. these technically legal opioids are out there. we just need to help the genie out of the bottle.

[resorcinol]

that is interesting and I think the hydromorphone analogs like metopon and acetylmorphone sound beautiful. but I think people should concentrate their efforts at discovering opioids that would be legal because of not being an analog of anything that is schedule I or II or anything scheduled at all. these things are interesting and all and would be great to do but an easy synth that could produce a legal opioid would be invaluable. in the US the analog act is supposed to only apply to things that are analogs of a CI or CII substance, not III or IV. these technically legal opioids are out there. we just need to help the genie out of the bottle.

This is a good point.

There are opioids, like this one (http://en.wikipedia.org/wiki/4-(p-Bromophenyl)-4-(dimethylamino)-1-phenethylcyclohexanol), for example, that are potent mu agonists and couldn't be lumped into the analog act b/c the bear no resemblance to a currently scheduled class of opioids. Somebody on BL coined the name bromidol for that one, but bromidol is already the name of another antipsychotic drug, so lets go with bromidinol instead :o

There's also herkinorin (http://en.wikipedia.org/wiki/Herkinorin). It's a Salvinorin A analog that is a potent mu agonist instead of a potent kappa agonist. In fact it has very little K activity compared to mu activity so it would likely be quite fun and not illegal to possess. The downside of this one is that it isn't an alkaloid, nor is it an organic acid, so it cannot be salted. This could be corrected by either synthing yet another analog that does have the basic amine group, but then it wouldn't be herkinorin anymore :p -- this is very possible though.

Hell, maybe getting rid of that ester at the bottom-most part of the herkinorin molecule in this pic --
http://upload.wikimedia.org/wikipedia/en/thumb/e/ef/Herkinorin.svg/200px-Herkinorin.svg.png

--would retain activity as a mu agonist. If so, it would then have an acidic carboxylic acid group, and could form salts. It would still be an oddity though, as most opioids are bases and form salts with acids (ie, morphine sulfate ... morphine base neutralized with sulfuric acid). This compound... desmethylherkinorin, would form salts with bases (like desmethylherkinorin magnesium ... desmethylherkinorin neutralized with magnesium hydroxide, a base).

Edit: Remember though, a whole new class of opioids could be taken down in the blink of an eye legal-wise by the DEA if they got popular, with emergency scheduling powers bullshit.

[Tea Time]

Herkinorin does sound very interesting. I seem to remember PGK talking about that a while back...